JP6048858B2 - Adhesive bone filler and adhesive bone filler kit - Google Patents

Description

The present invention relates to an adhesive bone filler and an adhesive bone filler kit.

  In Japan, the population is rapidly aging and the aging rate is expected to reach 30% in 2020 (that is, more than 30 million people are elderly). Elderly spine injury is a motor dysfunction directly linked to bedridden, and bedridden elderly patients have a high probability of transitioning to dementia, leading to long-term hospitalization. Among the spinal cord injuries, vertebral body compression fractures are particularly frequent and are often affected by osteoporosis, which increases markedly with age.

  There are 100 million people around the world at risk, and more than 2 million vulnerable fractures occur in the United States each year. According to a report on the prevalence of vertebral fractures in Japanese, 25% at 70-74 years old and 43% at 80-84 years old have vertebral body fractures or deformities, which is about twice that of the United States. ing.

  Therefore, there is an urgent need to develop a bone fusion vertebral body reconstruction device that minimizes invasion and maximizes the patient's own healing power.

  Conventional methods for treating vertebral body compression fractures include spinal fusion, in which the spine is fixed with a metal screw or rod to integrate the bone, and bone replacement is performed by injecting a bone filling agent into the vertebral body for early removal. Vertebroplasty for the purpose of pain has been performed.

  Since spinal fusion is highly invasive, there is a problem that a physical and economic burden is great for elderly people. On the other hand, in vertebroplasty, there is a balloon kaifoprity (BKP) in which a vertebral body compression fracture site is formed with a silicone balloon and a bone filling agent is introduced into the space (Non-patent Document 1). A spinal surgical instrument using the BKP technique is disclosed (Patent Document 1).

  Vertebroplasty has become the mainstream surgical method because of the low physical burden on patients. This vertebroplasty is a minimally invasive surgery, but when bone cement is used as a bone filler, the methyl methacrylate monomer contained in the bone cement leaks out of the vertebral body and causes complications such as pulmonary embolism and spinal cord injury. The case which causes is reported (nonpatent literature 2). Further, bone cement is non-absorbable (Patent Document 2). Further, there is a problem that the surrounding tissue is necrotized by a high polymerization heat.

  Further, although bone paste is resorbable, it may take about one week to reach the maximum strength, and there is a problem that the curing time is long and the strength in a short time cannot be realized (Non-patent Document 3). Furthermore, since most are inorganic components, there is a problem of not having adhesiveness to the cancellous bone inside the vertebral body (Patent Document 3). In addition, the calcium phosphate-based bone filling material has a problem in that it has no adhesiveness to the bone tissue immediately after application, in addition to the risk of leakage of the filling material due to a long hardening time of several hours or more.

JP 2012-85804 A JP 2001-510369 A Japanese Patent Application No. 10-539819

SPINE, 26, 151-156 (2001) Acta Radiologica, 48, 89-95 (2007) Journal of Materials Science Materials in Medicine, 6, 340-347 (1995)

  An object of the present invention is to provide an adhesive bone filler and an adhesive bone filler kit that have high adhesion to bone tissue, have a short adhesion time, and are highly resorbable. Another object of the present invention is to provide an adhesive bone filling material that has high biological safety and has a three-point bending strength that is moderately strong (1 MPa to 50 MPa).

  The present inventor uses a biopolymer (albumin, gelatin) as a liquid component and a solid-liquid two-component bone filling agent having an organic acid crosslinking agent / calcium phosphate as a solid component. And it discovered that the adhesive bone filling agent which adhere | attaches a bone tissue can be manufactured.

  In addition, it has been found that an adhesive bone filling agent that does not use a monomer can be produced as a solid-liquid two-component bone filling agent that uses a synthetic polymer as a liquid component and an organic acid crosslinking agent / calcium phosphate as a solid component. Completed the invention.

The adhesive bone filling material of the present invention is characterized by the following.
(1) An adhesive bone filling material that adheres to and hardens bone tissue,
and a liquid component comprising a buffer solution containing tetraamine-terminated polyethylene glycol (4 branch), a mixture of powder components comprising calcium phosphate and preparative risk succinimidyl citrate seen including,
The tetraamine-terminated polyethylene glycol (4 branches) is 5 mM to 40 mM, and the triskesin imidyl citrate is 25 mM to 75 mM;
P / L which is the ratio of the calcium phosphate (P (g)) to the liquid component (L (g)) is 2/1 to 3/1 .
(2) The calcium phosphate is α-tricalcium phosphate (α-TCP), α′-tricalcium phosphate (α′-TCP), β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP) ), Dicalcium phosphate dibasic (DCPD), tetracalcium phosphate monoxide (TeCP), hydroxyapatite (HAp), or calcium hydrogen phosphate .
(3) a metal element in said-phosphate calcium that is doped.
(4) The metal element is one or more of zinc, copper, strontium, silver, and titanium .
(5) The calcium phosphate is a particle of 10 to 1000 nanometers .
(6) to the liquid component or the powder component, that have been added alkali components.
(7) The calcium phosphate is α-tricalcium phosphate (α-TCP), and the α-tricalcium phosphate (α-TCP) is the powder material excluding the triskesin imidyl citrate. 50% to 80% of the mass .

The adhesive bone filling material of the present invention has high adhesion to bone tissue, has a short adhesion time, and can have high absorbability. Since the bone adhesiveness is high, leakage of the adhesive bone filling material from the bonded portion to the outside is prevented, and the risk of complications can be eliminated. There is also an advantage that the curing temperature is low. Further, the three-point bending strength can be set to an appropriate strength (1 MPa or more and 50 MPa or less).

  By setting the three-point bending strength to an appropriate strength, the risk of fracture of the vertebral bone adjacent to the surgical site can be greatly reduced. Polymethylmethacrylate bone cement becomes too hard and can cause further fractures of the surrounding vertebral bones. On the contrary, since the calcium phosphate-based bone filling material is brittle, there is a risk of fracture at the reinforced portion, while moderate strength is a great advantage. Moreover, biological safety is also high.

It is the schematic which shows an example of the adhesive bone filling material kit which is embodiment of this invention. It is process drawing which shows an example of the usage method of the adhesive bone filling material kit which is embodiment of this invention. It is process drawing which shows an example of the usage method of the adhesive bone filling material kit which is embodiment of this invention. It is explanatory drawing which shows an example of a crosslinking reaction when Tetramamine-terminated polyethylene glycol (TAPEG) and the organic acid crosslinking agent triscinimidyl citrate (TSC) are mixed. It is a visual image (photograph) of the shaping | molding sample after leaving still for 24 hours in 37 degreeC humidity environment. It is a visual image (photograph) of the shaping | molding sample after preparation. It is process drawing of a bone adhesiveness test. It is an electron micrograph which shows an example of the surface of the living bone mimic material used in this test. It is a photograph when the adhesive bone filling material (Test Example A1) is discharged from the syringe. It is the schematic which showed the outline | summary of the 3-point bending test. It is the graph which showed the three-point bending stress of the bone filler hardened | cured material and biopex by the adhesive bone filler of this invention. It is a graph which shows the TAPEG density | concentration dependence of the three-point bending stress of the bone substitute hardened | cured material by the adhesive bone filler of this invention. It is a graph which shows the TSC density | concentration dependence of the 3 point | piece bending stress of the bone filler hardened | cured material by the adhesive bone filler of this invention. It is a graph which shows the P / L ratio dependence of the three-point bending stress of the bone filler hardened | cured material by the adhesive bone filler of this invention. It is a graph which shows the (alpha) -TCP content dependence of the three-point bending stress of the bone substitute hardened | cured material by the adhesive bone filler of this invention. It is a graph which shows the TAPEG density | concentration dependence of the three-point bending stress of the bone substitute hardened | cured material by the adhesive bone filler of this invention.

(Embodiment of the present invention)
Hereinafter, an adhesive bone filling agent and an adhesive bone filling kit that are embodiments of the present invention will be described with reference to the accompanying drawings.
<Adhesive bone filling kit>
First, an adhesive bone filling kit that is an embodiment of the present invention will be described.

  FIG. 1 is a schematic view showing an example of an adhesive bone filling kit according to an embodiment of the present invention.

As shown in FIG. 1, an adhesive bone filling kit 11 according to an embodiment of the present invention includes a first container 12 enclosing a liquid component 21, a second container 13 enclosing a powder component 22, A third container 14 for producing an adhesive bone filling material by mixing the liquid component 21 and the powder component 22; and an injection container 15 for injecting the adhesive bone filling material into the bonding portion. It is roughly structured.
Here, the liquid component 21 is made of a buffer solution containing a water-soluble biocompatible polymer, and the powder component 22 is a calcium phosphate that is a first powder component and an organic acid bridge that is a second powder component. The adhesive bone filler is an adhesive bone filler according to an embodiment of the present invention, which will be described later.
<How to use adhesive bone filling kit>
Next, the usage method of the adhesive bone filling material kit which is embodiment of this invention is demonstrated.

  2 and 3 are process diagrams showing an example of a method for using the adhesive bone filling kit according to the embodiment of the present invention.

  First, as shown in FIG. 2A, the first container 12 is opened, the liquid component 21 is placed in the third container 14, the second container 13 is opened, and the powder component 22 is Place in third container 14.

  Next, as shown in FIGS. 2 (b) and 2 (c), after the liquid component 21 and the powder component 22 are thoroughly mixed in the third container 14 to form an adhesive bone filler 31. Into the injection container 15.

  Next, the compressed fracture portion of the bone 47 is inflated with a balloon to form a cavity portion 47c in the bone tissue defect portion / compressed fracture portion, and then bonded from the injection container 15 into the cavity portion 47c as shown in FIG. Sexual bone filling material 31 is injected.

  The bone 47 can be bonded and fixed by leaving it for a certain period of time.

In the above step, it is preferable to mix the powder component 22 into the liquid component 21 and mix well. Thereby, mixing operation can be simplified.
<Adhesive bone filler>
First, the adhesive bone filling material which is an embodiment of the present invention will be described.

  An adhesive bone filler 31 according to an embodiment of the present invention is an adhesive bone filler that mixes the liquid component 21 and the powder component 22 and then injects and applies the bone component to the bone tissue and adheres to the bone tissue. .

  The liquid component 21 is a buffer solution containing a water-soluble biocompatible polymer.

  The water-soluble biocompatible polymer is a water-soluble biocompatible biopolymer or synthetic polymer.

  The biopolymer is preferably albumin or gelatin. Thereby, biocompatibility and absorbability can be imparted to the produced adhesive bone cement.

  It is preferable that the albumin is one or more of serum albumin or genetically modified albumin of bovine, pig, horse or human. Specifically, the albumin can include human serum albumin (HSA). As a phosphate buffer solution containing a biopolymer, for example, a 42 w / v% phosphate buffer of human serum albumin (HSA) A solution (pH 8.0) (hereinafter abbreviated as 42 w / v% HSA) can be used.

  It is preferable that the gelatin is one or more gelatins of bovine, porcine, fish or human or genetically modified gelatin. In particular, fish gelatin is preferred because cod gelatin is liquid at room temperature even at high concentrations. Thereby, in addition to biocompatibility and absorbability, cell adhesiveness can be provided to the produced adhesive bone filling material.

  The synthetic polymer is preferably a polyether having an amino group at the side chain or terminal or a water-soluble polymer.

  The polyether having an amino group at the side chain or terminal is preferably 3 to 8 branched polyethylene glycol.

  Examples of the polyethylene glycol having 3 to 8 branches include pentaerythritol tetrapolyethylene glycol ether. Examples of the polyethylene glycol having an amino group at the side chain or terminal include tetraamine-terminated polyethylene glycol (four branches) (hereinafter referred to as TAPEG). Abbreviated). Examples of the water-soluble polymer include polypeptides, and examples of the polypeptide having an amino group at the side chain or terminal include polylysine.

  The powder component 22 is a mixed powder of calcium phosphate as a first powder component and an organic acid crosslinking agent as a second powder component.

  Calcium phosphate dissolves little by little and can reconstitute low crystalline hydroxyapatite in the body to increase strength.

  Examples of calcium phosphate include α-tricalcium phosphate (hereinafter abbreviated as α-TCP (<250 μm)) having a particle size of 250 μm or less. The smaller the particle size, the better. Nanoparticles are still preferred.

  The calcium phosphate is α-tricalcium phosphate (α-TCP), α′-tricalcium phosphate (α′-TCP), β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP), and dicalcium. A combination of one or more of phosphate dibasic (DCPD), tetracalcium phosphate monooxide (TeCP), hydroxyapatite (HAp), and calcium hydrogen phosphate is preferable. These calcium phosphates may be fired or unfired. Thereby, osteoconductivity and osteoinductive ability can be provided.

  The calcium phosphate is preferably doped with a metal element in order to impart bone forming ability. As the metal element to be doped, for example, one or more of zinc, copper, strontium, silver, and titanium is preferable. Thereby, osteogenesis can be promoted by activation of osteoblasts.

  Moreover, it is preferable that the said calcium phosphate is a particle | grain of 10-1000 nanometer. Thereby, the intensity | strength of hardened | cured material can be raised.

  The organic acid crosslinking agent is one or a combination of two or more crosslinking agents obtained by modifying all carboxyl groups of tartaric acid, malic acid, citric acid or succinic acid with N-hydroxysuccinimide or N-hydroxysulfosuccinimide. preferable. Thereby, the active ester of the crosslinking agent reacts with the amino group of the water-soluble biocompatible polymer contained in the liquid component and is cured. Examples of the citric acid crosslinking agent include trisuccinimidyl citrate (hereinafter abbreviated as TSC) in which the carboxyl group of citric acid is modified with N-hydroxysuccinimide. Further, examples of the malic acid crosslinking agent include disuccinimidyl malate obtained by modifying two carboxyl groups of malic acid with N-hydroxysuccinimide. Further, examples of the tartaric acid crosslinking agent include disuccinimidyl tartrate in which two carboxyl groups of tartaric acid are modified with N-hydroxysuccinimide.

  Furthermore, as a succinic acid crosslinking agent, disuccinimidyl succinate obtained by modifying two carboxyl groups of succinic acid with N-hydroxysuccinimide can be mentioned.

  FIG. 4 is an explanatory view showing an example of a crosslinking reaction when TAPEG and an organic acid crosslinking agent triscinimidyl citrate (TSC) are mixed. As shown in FIG. 4, by mixing the TAPEG aqueous solution and the citric acid crosslinking agent TSC, which is one of the solid components, the amino terminus of TAPEG is cross-linked with the dissolution of TSC in the aqueous solution. A polymer gel is formed within minutes.

An alkali component is preferably added to the liquid component 21 or the powder component 22. Thereby, the adhesion speed can be increased. The alkaline component is, for example, NaOH, NaHCO ₃ , KOH.

  When adding an alkaline component to the liquid component 21, an alkaline solution is mixed with the liquid component 21. As an alkaline solution, 0.1M NaOH sol. (ΜL).

  In addition, when an alkali component is added to the powder component 22, the powder component 22 is mixed with an alkali component obtained by powdering a substance dissolved in an alkaline solution.

  The ratio P / L of calcium phosphate (P (g)), which is the first powder component, and the liquid component (L (g)) satisfies the condition of 1/1 <P / L <3.5 / 1. It is preferable. Thereby, a moldability can be improved. In the case of 3.5 / 1 ≦ P / L, there is a risk of collapse. Further, in the case of P / L ≦ 1/1, there is a risk of non-uniformity.

  An adhesive bone filling material 31 according to an embodiment of the present invention is an adhesive bone filling material that adheres to and hardens bone tissue by being injected and applied to, for example, a bone tissue defect portion or a compression fracture portion. The composition includes a mixture of a liquid component 21 composed of a buffer solution containing a water-soluble biocompatible polymer and a powder component 22 containing calcium phosphate and an organic acid cross-linking agent. Is short and the absorbency can be increased.

  Further, the three-point bending strength can be set to an appropriate strength (1 MPa or more and 50 MPa or less). By setting the three-point bending strength to an appropriate strength of 1 MPa or more and 50 MPa or less, the risk of fracture of the vertebral bone adjacent to the surgical site can be greatly reduced. Polymethylmethacrylate bone cement becomes too hard and can cause further fractures of the surrounding vertebral bones. On the contrary, since the calcium phosphate bone filler is brittle, there is a risk of fracture at the reinforcing portion. On the other hand, if the strength is appropriate, these fears can be reduced, which is a great advantage in practical use.

  The adhesive bone filling material 31 according to an embodiment of the present invention has a configuration in which the water-soluble biocompatible polymer is a biopolymer or a synthetic polymer having water-soluble biocompatibility, and thus has high dispersibility in a buffer solution. A liquid component can be prepared, and it can be used as an adhesive bone filler that is highly safe for living bodies.

  The adhesive bone filling material 31 according to the embodiment of the present invention can increase the absorbability because the biopolymer is albumin or gelatin.

  The adhesive bone filling material 31 according to an embodiment of the present invention has a structure in which the albumin is one or more of serum albumin or recombinant albumin of bovine, pig, horse or human, Can be high. Moreover, cell adhesiveness can be improved.

  The adhesive bone filling material 31 according to an embodiment of the present invention has a structure in which the gelatin is one or more of bovine, porcine, fish or human, or genetically modified gelatin. In addition, cell adhesion can be enhanced.

  The adhesive bone filling material 31 according to an embodiment of the present invention has a structure in which the synthetic polymer is a polyether having a side chain or an amino group at the terminal or a water-soluble polymer. By crosslinking the amino side chain or amino terminal of the molecule, the strength of the bone filling material itself can be increased.

  The adhesive bone filling material 31 according to the embodiment of the present invention has a structure in which the polyether having an amino group at the side chain or terminal is a polyethylene glycol having 3 to 8 branches. By crosslinking the amino terminus, the strength of the bone filling material itself can be increased.

  In the adhesive bone filling material 31 according to an embodiment of the present invention, the 3 to 8 branched polyethylene glycol is pentaerythritol tetrapolyethylene glycol ether, and the polyethylene glycol having an amino group at a side chain or a terminal is tetraamine-terminated. Since it is the structure which is polyethyleneglycol (4 branches), a crosslinked structure can be formed by bridge | crosslinking the amine terminal of polyether with an organic acid crosslinking agent, and the intensity | strength of the bone filling material itself can be raised.

  In the adhesive bone filling material 31 according to the embodiment of the present invention, the calcium phosphate is α-tricalcium phosphate (α-TCP), α′-tricalcium phosphate (α′-TCP), β-tricalcium phosphate. (Β-TCP), octacalcium phosphate (OCP), dialcalcium phosphate dibasic (DCPD), tetracalcium phosphate monooxide (TeCP), hydroxyapatite (HAp), or a combination of two or more of calcium hydrogen phosphate Therefore, the adhesiveness to the bone tissue can be increased.

  In the adhesive bone filling material 31 according to an embodiment of the present invention, the organic acid crosslinking agent is modified with N-hydroxysuccinimide or N-hydroxysulfosuccinimide on all carboxyl groups of tartaric acid, malic acid, succinic acid or citric acid. Since it is the structure which is 1 type, or 2 or more types of a crosslinking agent, adhesiveness can be provided to a bone filling agent.

  Since the adhesive bone filling material 31 according to the embodiment of the present invention has a configuration in which an alkali component is added to the liquid component or the powder component, the bonding speed can be increased and the bonding time can be shortened. .

  In the adhesive bone filling material 31 according to the embodiment of the present invention, P / L, which is the ratio of the first powder component (P (g)) to the liquid component (L (g)), is 1/1. Since it is the structure which satisfy | fills the conditions of <P / L <3.5 / 1, the adhesiveness with respect to a bone tissue is high, the adhesion | attachment time is short, and absorptivity can be made high. Further, the three-point bending strength can be set to an appropriate strength (1 MPa or more and 50 MPa or less).

  An adhesive bone filling kit 11 according to an embodiment of the present invention includes a first container 12 enclosing a liquid component 21, a second container 13 enclosing a powder component 22, a liquid component 21 and a powder component. 22, a third container 14 for producing an adhesive bone filling material 31, and an injection container 15 for injecting the adhesive bone filling material 31 into an adhesive part, wherein the liquid component is water-soluble. This is composed of a buffer solution containing a biocompatible polymer, and the powder component is a mixed powder of calcium phosphate as the first powder component and organic acid crosslinking agent as the second powder component. Adhesion treatment can be performed easily and promptly without the need for other instruments / reagents.

  The adhesive bone filling material and the adhesive bone filling material kit that are embodiments of the present invention are not limited to the above-described embodiments, and may be implemented with various modifications within the scope of the technical idea of the present invention. Can do. Specific examples of this embodiment are shown in the following examples. However, the present invention is not limited to these examples.

Example 1
<Optimization test of liquid / solid (P / L)>
In the following manner, the bone filling agent forming ability at various mixing ratios of liquid / solid (P / L) was examined, and the optimum condition of liquid / solid (P / L) was examined.

  First, as a liquid component (L), 42 w / v% HSA or 30 w / v% cod gelatin using human serum albumin (HSA, manufactured by Sigma), α-TCP (Wako Pure Chemical Industries) as calcium phosphate of the powder component (P) TSC was prepared as an organic acid cross-linking agent.

  Next, the mixing ratio (P / L) of 42 w / v% HSA or 30 w / v% cod gelatin, which is the liquid component (L), and α-TCP (<250 μm), which is the powder component (P), is changed to P /L=3.5/1 (Test Examples 1 and 6), 3/1 (Test Examples 2 and 7), 2/1 (Test Examples 3 and 8), 1/1 (Test Examples 4 and 9), 1 / 2 (Test Examples 5 and 10) were prepared. In each test example, as shown in Table 1, the amount of TSC added and the amount of alkali added (0.1 M NaOH sol. (ΜL)) were also changed.

  Table 1 shows the observation results of the preparation conditions and moldability of the adhesive bone filler prepared using 42 w / v% HSA.

Table 2 shows the preparation conditions and moldability observation results of the adhesive bone filler prepared using 30 w / v% cod gelatin.

Next, five cylindrical shaped samples having a diameter of 7 mm and a height of 14 mm were formed using these adhesive bone fillers.

  Next, each molded sample of the adhesive bone filling material prepared using 42 w / v% HSA was allowed to stand in a 37 ° C. humid environment for 24 hours.

  FIG. 5 is a visual image (photograph) of a molded sample after standing for 24 hours in a 37 ° C. humid environment. As can be seen from the photograph, the moldability of the molded samples of P / L = 1.5 / 1 (Test Example 2), 2/1 (Test Example 3), and 3/1 (Test Example 4) after standing still is It was good.

  On the other hand, after standing, the moldability of the molded sample with P / L = 1/1 (Test Example 1) became non-uniform. This is because α-TCP is not uniform.

  Moreover, the molded sample of P / L = 3.5 / 1 (Test Example 5) collapsed. This is because α-TCP could not be uniformly dispersed in the liquid and the shape could not be maintained.

  Therefore, in the case of 42 w / v% HSA, it became clear that the condition of 1/1 <P / L <3.5 / 1 is optimal.

  Next, each molded sample was prepared using an adhesive bone filler prepared using 30 w / v% cod gelatin.

  FIG. 6 is a visual image (photograph) of the molded sample after preparation. As can be seen from the photograph, P / L = 1.5 / 1 (Test Example 7), 2/1 (Test Example 8), 3/1 (Test Example 9), 3.5 / 1 (Test Example 10). The moldability of the molded sample was good.

  On the other hand, after standing, the molded sample of P / L = 1/1 (Test Example 6) was fragile. This is because the physical properties of cod gelatin became dominant because the α-TCP content was not sufficient.

Therefore, in the case of 30 w / v% cod gelatin, it became clear that the condition of 1/1 <P / L was optimal.
<Bone adhesion test>
Next, the bone adhesion test was performed using the adhesive bone filling material using 42 w / v% HSA.

  FIG. 7 is a process diagram of a bone adhesion test.

  A living bone mimetic material was used as the test piece 52 for the bone adhesion test.

  The living bone mimicking material was prepared by immersing ivory (diameter 6 mm, thickness 0.3 mm, disk shape) in a 25% phosphoric acid solution for 180 seconds, washing with a large amount of water, and drying.

FIG. 8 is an electron micrograph showing an example of the surface of the living bone mimic material used in this test.
<Adhesion test>
First, ivory (diameter 6 mm, thickness 0.3 mm, disk shape) was used for the test piece 52. Before the adhesion test, the ivory was immersed in a 25% phosphoric acid solution for 180 seconds, washed with a large amount of water and dried. For the adhesion test, a test piece (ivory) was attached to the surface 51 a of the cylindrical polymethylmethacrylate plastic rod 51.

  Next, a cylindrical silicone 53 having an inner diameter of 7 mm and a height of 14 mm was covered.

  Next, the adhesive bone filling material 31 was introduced into the cylinder of the silicone 53. As the adhesive bone filling material 31, an adhesive bone filling material P / L = 3/1 using 42 w / v% HSA, bone cement (commercial product), and Biopex (manufactured by HOYA Corporation) were used.

  Next, the adhesive strength of the adhesive bone filler or the like to the test piece (ivory) 52 was examined by a texture analyzer.

  Table 3 shows the results of the adhesive strength of these adhesive bone fillers and the like.

P / L = 3/1 (Test Example 4) had higher adhesive strength than Biopex. Further, the bone cement has a high adhesive strength of 0.8 MPa, but it is not preferable because it is a composite and does not exhibit absorbability.
<Three point bending strength test>
First, a plate-shaped test piece having a length of 64 mm, a width of 10 mm, and a thickness of 4 mm was prepared.

  Next, the three-point bending strength of the molded sample was measured by an autograph. Commercially available bone cement and biopex were used as controls.

  Table 4 shows the results of the three-point bending strength test.

P / L = 3/1 (Test Example 4) had a low three-point bending strength compared to biopex and bone cement, but the bending strength exceeded that of biopex by changing the composition of the powder component. It was.

<Liquid / Solid (P / L) Optimization Test 2 (Test Examples A1 to A20: Run # A1 to A20)>
In the following manner, the bone filling agent forming ability at various liquid / solid (P / L) mixing ratios was examined.

  First, TAPEG was dissolved in 0.1 M phosphate buffer (pH 6.0) to prepare a TAPEG solution (liquid component (L)).

  Next, α-TCP, nanoapatite particles (spherical-average particle size of 40 nm, manufactured by Softela Co., Ltd.) and TSC were weighed and mixed well with a pencil stirrer as the solid component (P). This mixed powder was added to a TAPEG solution dissolved in 0.1 M phosphate buffer (pH 6.0), which is a liquid component (L), and stirred and mixed with a pencil stirrer to prepare an adhesive bone filler.

  FIG. 9 is a photograph when the adhesive bone filling material (Test Example A1) is discharged from the syringe.

  Next, the adhesive bone filling material was applied by the method described above, and the three-point bending strength was measured.

  Table 5 shows the preparation conditions of the prepared adhesive bone filling material and the measurement results of the three-point bending strength (Bending strength).

As shown in Table 5, by controlling the P / L ratio, TAPEG concentration, and TSC content, the three-point bending strength (bending strength) could be controlled to 1.28 MPa or more and 6.11 MPa or less.

(Evaluation test 1 for adhesive bone filler)
(Experiment)
Nano HAp: Nano-SHAp (spherical-average particle size 40 nm) (manufactured by Sofcella) was prepared as calcium phosphate of the powder material, and synthetic DST (Disuccinimidyl tartarate) was prepared as the organic acid crosslinking agent. A predetermined amount of DST and nano HAp were weighed and mixed well with a pencil stirrer to obtain a mixed powder. Add this mixed powder to a tube containing HSA (Human serum albumin, Sigma-Aldrich, 0.1M PBS pH6.0), a liquid component, and stir for 10 seconds with a pencil stirrer to give an adhesive bone filler. Obtained. By this method, a plurality of adhesive bone filling agents were obtained by changing the mixing ratio of HAS, DST, and nanoHAp.

The adhesive bone adhesive was molded into a cylindrical (φ7 mm, height 14 mm) silicone tube. It was allowed to stand at 37 ° C. for 1 day to cure, taken out of the silicone mold and observed. At that time, the curing time was qualitatively evaluated.
(result)
Table 6 (Test Nos. 1 to 9) and Table 7 (Test No. 1) show the state of the obtained adhesive bone filling material (uniformity and ease of injection) and the state of the cured bone filling material. 10 to 18) and Table 8 (Test Nos. 19 to 27).

In this adhesive bone filling material, when the concentration of HSA, which is a liquid component, is high (40 w / w%), the powder component containing HSA, DST, and nanoHAp is less likely to be uniformly mixed, and there is a tendency for hardening to be accelerated. However, contrary to expectations, there was a tendency that the smaller the DST amount, the faster the curing and the stronger the hardness of the bone filler cured material. Among the trials, it was confirmed that Test No. 5 was excellent in handleability of the adhesive bone filling material, had good hardness after 24 hours, and had the best balance in terms of practicality.

<Evaluation test 2 of adhesive bone filler>
(Experiment)
The test was conducted under the same conditions as in the above-described adhesive bone filler evaluation test 1 except that synthetic DSM (Disuccinimidyl malate) was used as the organic acid crosslinking agent instead of DST.
(result)
Table 9 shows the results of evaluating the state of the obtained adhesive bone filling material and the state of the cured bone filling material.

This adhesive bone filling material using DSM had a longer setting time than DST and was easy to mold. There was a tendency for the adhesive bone filler to have a lower viscosity than the same amount of DST. From the handleability of the adhesive bone filling material and the hardness of the cured bone filling material after 24 hours, it was revealed that Test No. 3 and No. 4 were balanced.

  Therefore, it became clear that DSM, which is a highly hydrophobic organic acid crosslinking agent, is more useful as a powder component of an adhesive bone filler than DST. From this result, when TSC, which is a highly hydrophobic organic acid cross-linking agent, is used as the powder component of the adhesive bone filling material, the handleability of the adhesive bone filling material and the hardness of the cured bone filling material are similarly reduced. It became clear that it was excellent.

<Measurement of mechanical strength of HSA bone filling material>
(Experiment)
The test piece for the three-point bending test uses DSM and nanoHAp as the powder material (P), 35w / w% HSA (0.1M PBS pH6) as the liquid material (L), and this P / L ratio is 2 / 1 so that DSM was 125 mM, mixed with nano HAp, and mixed well with a pencil stirrer to obtain a mixed powder. After this mixed powder is added to the HSA solution, it is stirred with a pencil stirrer to produce an adhesive bone filler. After filling this adhesive bone filler into a 40 x 10 x 4 mm silicone mold, sandwiched between glass plates Molded. After allowing to stand at 37 ° C. for 1 day and curing to obtain a cured bone filler, a three-point bending test was performed on the cured bone filler.

An outline of the three-point bending test is shown in FIG. In the three-point bending test, Shimadzu Autograph AGS-H was used and evaluated with a 1KN load cell. As shown in FIG. 10, the test piece was supported between fulcrums having a constant radius of curvature R, a load was applied to the center with a pressure wedge, and the load when the test piece was broken was defined as strength.
(result)
The results are shown in FIG. This bone filler cured product using HSA had a bending stress of 1.7 MPa (± 0.2). On the other hand, since the strength of commercially available bone filler Biopex (made by Hoya Co., Ltd.) is more than 4 times higher, it is considered necessary to study other biocompatible polymers in order to improve bending stress. It was.

<Measurement of mechanical strength of TAPEG bone filler>
(Experiment)
The specimen of the three-point bending test uses TSC (Trisuccinimidyl citrate) and nano HAp, and α-TCP (α-Tricalcium phosphate) as the powder material (P), and TAPEG / α as the liquid material (L). 0.1M PBS (pH 6) (TAPEG: Tetraamine terminated polyethylene glycol (MW: 20,000) (manufactured by NOF Corporation) was used.

  For the powder material, the ratio of α-TCP and nano HAp was determined, excluding the mass of TSC. The test piece was prepared by weighing TSC, nano HAp and α-TCP and mixing them well with a pencil stirrer. Add this mixed powder to the TAPEG solution and stir with a pencil stirrer to make an adhesive bone filler, fill this adhesive bone filler into a 40 x 10 x 4 mm silicone tube, and mold with a glass plate did. After allowing to stand at 37 ° C. for 1 day and curing to obtain a cured bone filler, a three-point bending test was performed on the cured bone filler.

(Result-1) Evaluation of TAPEG concentration effect on three-point bending strength
The P / L ratio was set to 2.5 / 1, and the α-TCP was evaluated for the TAPEG dependence of the three-point bending strength so that the powder material would be 40% of the mass excluding TSC. As shown in FIG. 12, it was confirmed that 25 mM TAPEG has the highest bending stress.

(Result-2) Evaluation of the effect of TSC concentration on three-point bending strength
The P / L ratio was set to 2.5 / 1, and α-TCP was evaluated for the TSC concentration dependency of the three-point bending strength so that the mass of the powder material was 40% excluding TSC. As shown in FIG. 13, it was confirmed that the bending stress was highest when the TSC concentration was 50 mM.

(Result-3) Evaluation of the effect of P / L ratio on the three-point bending strength α-TCP shows the TSC concentration dependence of the three-point bending strength so that it is 40% of the mass of the powder material excluding TSC. evaluated. As shown in FIG. 14, it was confirmed that the bending stress was highest when the P / L ratio was 2.5 / 1. In a preliminary experiment, P3.5 / L1 was too powdery and could not be molded.

(Result-4) Evaluation of the effect of α-TCP on the three-point bending strength
The P / L ratio is fixed at 2.5 / 1, and α-TCP is 50, 60, 70, 75, 80% of the mass of the powder material excluding TSC, and the three-point bending strength depends on the TSC concentration. Sex was evaluated. Bending stress was also measured under the same conditions for Biopex with α-TCP content of 75%. As shown in FIG. 15, it was confirmed that 70% of the α-TCP content had the highest bending stress and high reproducibility.

(Result-5) Optimization of conditions of bone filler components on three-point bending strength
With 25 mM TAPEG / 50 mM TSC + (nanoHAp + 70% α-TCP), the P / L ratio of 2.5 / 1 was suggested to have the highest bending stress, so a three-point bending test was performed under these conditions. The P / L ratio was set to 2.5 / 1. As shown in FIG. 16, it was confirmed that 25/1 TAPEG / 50 mM TSC + (nanoHAp + 70% α-TCP) and Powder / Liquid ratio of 2.5 / 1 had the highest bending stress.

  The adhesive bone filling material and adhesive bone filling material kit of the present invention relates to an adhesive bone filling material and an adhesive bone filling material kit that have high adhesion to bone tissue, a short bonding time, and high absorbability. This adhesive bone filler has a shorter bonding time than bone cement and bone paste in the treatment of compression fractures, has high strength and high adhesive properties, and can be used with high absorbency. It can be used in the medical device / material / equipment industry.

DESCRIPTION OF SYMBOLS 11 ... Adhesive bone filler kit, 12 ... 1st container, 13 ... 2nd container, 14 ... 3rd container, 15 ... Injection | pouring container, 21 ... Liquid component, 22 ... Powder component, 23 ... X-ray Detector, 24 ... Stand, 31, 32 ... Adhesive bone filler, 47 ... Bone, 47c ... Cavity, 51 ... Polymethylmethacrylate plastic rod, 51a ... Surface, 52 ... Test piece, 53 ... Cylindrical silicone

Claims (7)

An adhesive bone filling agent that adheres to and hardens bone tissue,
and a liquid component comprising a buffer solution containing tetraamine-terminated polyethylene glycol (4 branch), a mixture of powder components comprising calcium phosphate and preparative risk succinimidyl citrate seen including,
The tetraamine-terminated polyethylene glycol (4 branches) is 5 mM to 40 mM, and the triskesin imidyl citrate is 25 mM to 75 mM;
The adhesive bone filling material , wherein P / L which is a ratio of the calcium phosphate (P (g)) and the liquid component (L (g)) is 2/1 to 3/1 . The calcium phosphate is α-tricalcium phosphate (α-TCP), α′-tricalcium phosphate (α′-TCP), β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP), and dicalcium. The adhesive bone filler according to claim 1, which is one or a combination of two or more of phosphate dibasic (DCPD), tetracalcium phosphate monoxide (TeCP), hydroxyapatite (HAp), and calcium hydrogen phosphate. . Adhesion bone filling agent according to claim 1 or 2 metal element is characterized that you have been doped to said calcium phosphate. 4. The adhesive bone filler according to claim 3, wherein the metal element is one or more of zinc, copper, strontium, silver, and titanium . The adhesive bone filler according to any one of claims 1 to 4 , wherein the calcium phosphate is a particle of 10 to 1000 nanometers . Wherein the liquid component or the powder component, adhesion bone filling agent claimed in any one of 5, wherein that you have been added alkali components. The calcium phosphate is α-tricalcium phosphate (α-TCP), and the α-tricalcium phosphate (α-TCP) is 50 masses of the powder material excluding the trisuccinimidyl citrate. The adhesive bone filling material according to claim 1 , wherein the adhesive bone filling material is in a range of% to 80% .